EP1140859A2 - Derives bicycliques (hetero)aryl aryl, leur preparation et leur utilisation comme inhibiteurs de protease - Google Patents

Derives bicycliques (hetero)aryl aryl, leur preparation et leur utilisation comme inhibiteurs de protease

Info

Publication number
EP1140859A2
EP1140859A2 EP99968917A EP99968917A EP1140859A2 EP 1140859 A2 EP1140859 A2 EP 1140859A2 EP 99968917 A EP99968917 A EP 99968917A EP 99968917 A EP99968917 A EP 99968917A EP 1140859 A2 EP1140859 A2 EP 1140859A2
Authority
EP
European Patent Office
Prior art keywords
hydroxy
phenyl
alkyl
carboxamidine
chj
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99968917A
Other languages
German (de)
English (en)
Inventor
Darin Arthur Allen
Jason M. Hataye
Witold N. Hruzewicz
Aleksandr Kolesnikov
Richard Laurence Mackman
Roopa Rai
Jeffrey R. Spencer
Erik J. Verner
Wendy B. Young
William Dvorak Shrader
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Axys Pharmaceuticals Inc
Original Assignee
Axys Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Axys Pharmaceuticals Inc filed Critical Axys Pharmaceuticals Inc
Publication of EP1140859A2 publication Critical patent/EP1140859A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel protease inhibitors .
  • uPA Urokinase-type plasminogen activator
  • Inhibitors of uPA have been postulated to be of therapeutic value in treating cancer. Inhibitors of these serine proteases also tend to be inhibitors of the closely related blood-clotting enzymes.
  • One such blood-clotting enzyme is Factor Xa .
  • FXa Factor Xa
  • Kunitada and Nagahara in Current Pharmaceutical Design, 1996, Vol. 2, No .5 report amidinobenzyl compounds as FXa and thrombin inhibitors.
  • Disclosed in U.S. Patent No. 5,576,343 are aromatic amidine derivatives and salts thereof, as reversible inhibitors of FXa.
  • These compounds comprise amidino substituted indolyl, benzofuranyl, benzothienyl, benzimidazolyl , benzoxazoyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl groups, attached to a substituted phenyl ring by an alkylene group having from 1 to 4 carbon atoms .
  • the present invention relates to compounds of Formula
  • A represents a saturated, unsaturated, or a partially unsaturated bicyclic heterocyclic ring structure substituted with R 6 , R 7 , R 8 , R 9 , and R 20 ;
  • B represents
  • R 1 represents OH, halogen, COOH, COO-C, . , alkyl, O-(CH 2 ) 0 _ 1 - Ph, N(R 10 ) 2 , CH 2 OR 10 , C 1 _ 6 halogenated alkyl, 0- (CH,) ⁇ .-CO- N(R 10 ) 2 , SC._ 4 alkyl, NHSO a C.
  • R 2 , R 3 , R 4 , and R 5 independently at each occurance represent H, SH, OR 10 , halogen, COOR 10 , C0NR n R 12 , optionally substituted aryl, optionally substituted heterocyclyl, C._ 14 cycloalkyl-C._ 4 alkyl, i alkyl aryl, optionally substituted C.._ 14 straight chain, branched or cyclo alkyl, (CH,) . .4 -NR 33 R", (CH,), ., -
  • R and R 9 independently at each occurance represents H, halogen, cyano, C x _ 4 alkyl, C 1-4 halogenated alkyl, N0 2 , 0- aryl or OR 11 ;
  • R x independently at each occurance represents H, (CH ) aryl, C 1-4 halo alkyl, or C ⁇ straight chain, branched or cyclo alkyl, and alternatively, when one atom is substituted with two R 10 groups, the atom along with the R 10 groups can form a five to 10 membered ring structure; R 11 and R 12 independently at each occurance represent H or C, 1-4. alkyl; ,20
  • R represents R , C ⁇ -alkyl, (CH 2 ) -biphenyl , [CH, -Ph- N(S0 2 -C 1 _ 2 -alkyl) 2 , [CE -NH-C(0)-R ' ;CH 2 ) 1 _ 4 -NH-S0 2 -R ⁇ halogen, COOR 10 , (CH 2 ) 14 -Ph-N(S0 2 -C 1 _ 2 alkyi; C(0)-R 24 , (CH 2 ) 1 _ 4 -NR 10 -SOêt 2-R 24 [CH, _ -CON(R 10 )
  • R 24 represents R 10 , (CH 2 ) x 4 -optionally substituted aryl
  • R represents (CH 2 ) . 2 -Ph-0- (CH 2 ) 0 _ 2 -het-R , C(0)-het, CH.-Ph- CH 2 -het-(R 30 ). 3 ; (CH 2 ) . 4 -cyclohexyl-R 31 , CH 2 -Ph-0-Ph- (R 30 ) . ,,
  • R 32 represents H, C (0) -CH 2 -NH 2 , or C (0) -CH (CH (CH 3 ) 2 ) -NH 2 ;
  • R 33 and R 34 independently at each occurance represent R 10 , (CH 2 ) 04 -Ar, optionally substituted aryl, (CH 2 ) 04 optionally substituted heteroaryl, (CH 2 ) 14 -CN, (CH 2 ) 1-4 -N (R 10 ) 2 , (CH 2 )._ 4 - OH, (CH 2 ) 1 _ 4 -SO 2 -N(R 10 ) 2 ; alternatively, R 33 and R 34 along with the nitrogen atom that they are attached to forms a 4 to 14 atom ring structure selected from
  • R 35 represents R 10 , S0 2 -R 10 , COR 10 , or CONHR 10 ; E represents a bond, S(O) 02 , 0 or NR 10 ; W., W 2 , 3 and W 4 independently represent C or N; and Q. Q 1 / Q 2 Q 3 .
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for treating or preventing a thromboembolic disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • A-B its prodrug forms, or pharmaceutically acceptable salts thereof, wherein
  • A represents a saturated, unsaturated, or a partially unsaturated bicyclic heterocyclic ring structure substituted with R 6 , R 7 , R 8 , R 9 , and R 20 ;
  • R 1 represents OH, halogen, COOH, C00-C._ 4 alkyl, O-(CH 2 ) 0 _.-
  • R 2 , R 3 , R 4 , and R 5 independently at each occurance represent H, SH, OR 10 , halogen, COOR 10 , CONR ⁇ R 12 , optionally substituted aryl, optionally substituted heterocyclyl, C 4 14 cycloalkyl-C.
  • R 6 and R 9 independently at each occurance represents H, halogen, cyano, C. 4 alkyl, C. 4 halogenated alkyl, N0 2 , 0- aryl or OR 11 ;
  • R 7 and R 8 independently at each occurance represent OH
  • R 10 independently at each occurance represents H, (CH 2 ) 02 - aryl, C. ⁇ 4 halo alkyl, or C. ⁇ . straight chain, branched or cyclo alkyl, and alternatively, when one atom is substituted with two R 10 groups, the atom along with the R 10 groups can form a five to 10 membered ring structure; R 11 and R 12 independently at each occurance represent H or
  • R represents R , C._ 4 -alkyl, (CH 2 ). .3 -biphenyl. (CH 2 )._ 4 -Ph- N(S0 2 -C 1 _ 2 -alkyl) 2 , (CH 2 )._ 4 -NH-C(0)-R 24 , (CH 2 ). . . -NH-SO.-R halogen, COOR 10 , :CH 2 ).. 4 -Ph-N(S0 2 -C.
  • R 24 represents R [CH 2 ) 14 -optionally substituted aryl
  • R 28 represents (CH -Ph-O- (CH n. ,-het-R 3 C(0)-het, CH-Ph-
  • R represents H, C (0) -CH-NH., or C (0) -CH (CH (CH. -NH,
  • R and R 34 independently at each occurance represent R 10 , (CH, -Ar, optionally substituted aryl, (CH 0-4 optionally substituted heteroaryl, (CHJ. -CN, (CHJ. -N(R10) [CH,
  • R represents R , SO -R , COR , or CONHR
  • E represents a bond, S(O), 0 or NR
  • W., W 2 , W 3 and W 4 independently represent C or N; and Q. Q 1 / Q 2 Q 3 .
  • R 3 , R 4 , and R 5 represents H
  • R 1 OH
  • R 7 amidine
  • R 2 , R 3 , R 4 , R 5 , and R 20 each represent H
  • R 6 , R 8 , R 9 are independently chosen from H, CH 3 , and halogen, then only one of R 6 , R , and R 9 represents H; (iii!
  • R 1 represents OH, halogen, COOH, COO-C._ 4 alkyl, 0- (CH 2
  • N(R l ⁇ ) SC alkyl
  • NHS0 2 C._ 4 alkyl S0 2 -OH, 0-S0 2 -OH, 0-S0 2 -
  • R ⁇ R , R , and R independently at each occurance represent H, SH, OR 10 , halogen, COOR 10 , CONR ⁇ R 12 , optionally substituted aryl, optionally substituted heterocyclyl, C 4 _ 14 cycloalkyl-C 1 _ 4 alkyl, C 14 alkyl aryl, optionally substituted C, , notice straight chain, branched or cyclo alkyl,
  • R and R independently at each occurance represents H, halogen, cyano, C. 4 alkyl, C._ 4 halogenated alkyl, N0 2 , 0- aryl or OR 11 ;
  • R 20 represents R 24 , C 14 -alkyl, (CH 2 ) ._ 3 -biphenyl , (CH 2 ) 14 -Ph- N(S0 2 -C 12 -alkyl) 2 , (CH 2 ) . 4 -NH-C (0) -R 24 , (CH 2 ) . 4 -NH-S0 2 -R 24 , halogen, COOR 10 , (CH 2 ) . 4 -Ph-N(S0 2 -C. 2 alkyl) , (CH 2 ) . 4 -NR 10 - C(0)-R 24 , (CH 2 ) 14 -het, (CH 2 ) ._ 4 -C0N (R 10 2 '
  • R 24 represents R 10 , (CH 2 ) 14 -optionally substituted aryl
  • R 28 represents (CH 2 ) . 2 -Ph-0- (CH 2 ) 0 _ 2 -het-R 30 , C(0)-het, CH 2 -Ph-
  • R 32 represents H, C (0) -CH 2 -NH 2 , or C (0) -CH (CH (CHJ ) -NH 2 ;
  • R J and R 34 independently at each occurance represent R 10 , (CH, -Ar, optionally substituted aryl, (CH ) optionally substituted heteroaryl, (CH 2 ) 14 -CN, (CH 2 ) 14 -N(R [CH,
  • R represents R SO.-R ⁇ COR , or CONHR
  • R 1 represents OH, halogen, COOH, COO-C._ 4 alkyl, 0-(CH 2 )._.- Ph, N(R 10 ) 2 , CH 2 OR 10 , C., 6 halogenated alkyl, 0- (CH 2 ) . . .-C0- N(R 10 ) 2 , SC ⁇ alkyl, NHS0 2 C._ 4 alkyl , S0 2 -0H, 0-S0 2 -0H, 0-S0 2 - 0-C. .4 alkyl, 0P(0) (0H) 2 , or OP0 3 C. .4 alkyl;
  • R 2 , R 3 , R 4 , and R 5 independently at each occurance represent H, SH, OR 10 , halogen, COOR 10 , CONR ⁇ R 12 , optionally substituted aryl, optionally substituted heterocyclyl, C 4 14 cycloalkyl-C._ 4 alkyl, C 1.4 alkyl aryl, optionally substituted C.._ 14 straight chain, branched or cyclo alkyl, O-(CH 2 ) 2 _ 6 -NR 10 -(CH 2 ) 0 . 3 -R 24 , NR 10 R 24 , (CH 2 ) ._ 4 -NR 33 R 34 , (CH 2 ).
  • R 6 and R 9 independently at each occurance represents H, halogen, cyano, C 14 alkyl, C.._ 4 halogenated alkyl, N0 2 , 0- aryl or OR 11 ;
  • R 10 independently at each occurance represents H, (CH 2 ) 02 - aryl , C 14 halo alkyl, or C x 14 straight chain, branched or cyclo alkyl, and alternatively, when one atom is substituted with two R 10 groups, the atom along with the R 10 groups can form a five to 10 membered ring structure; R 11 and R 12 independently at each occurance represent H or
  • R 20 represents R 24 , C 14 -alkyl, (CH 2 ) ..-biphenyl , (CH 2 ) 14 -Ph-
  • R 24 represents R 10 , (CH 2 ) ..-optionally substituted aryl, (CH 2 ) ⁇ 4 OR 10 , CO-(CH 2 ) 12 -N(R 10 ) 2 , CO (CH 2 ) . 4 -OR 10 , (CH 2 ) . 4 -COOR 10 , (CH 2 ) 0 _ 4 -N(R 10 ) 2 , S0 2 R 10 , COR 10 , CON(R 10 ) 2 , (CH 2 ) 04 -aryl-COOR 10 , (CH 2 ) 04 -aryl-N(R 10 ) 2 , or (CH 2 ) . 4 -het-aryl ;
  • R 28 represents (CH 2 ) ._ 2 -Ph-0- (CH 2 ) 2 -het-R 30 , C(0)-het, CH 2 2-Ph-
  • R 32 represents H, C (0) -CH 2 -NH 2 , or C (0) -CH (CH (CH 3 ) 2 ) -NH 2 ;
  • R 33 and R 34 independently at each occurance represent R 10 , (CH 2 ) 04 -Ar, optionally substituted aryl, (CH 2 ) 04 optionally substituted heteroaryl, (CH 2 ) 14 -CN, (CH 2 ) .
  • R 33 and R 34 along with the nitrogen atom that they are attached to forms a 4 to 14 atom ring structure selected from tetrahydro-lH-carboline; 6,7- Dialkoxyoxy-2-substituted 1,2,3, 4-tetrahydro- isoquinoline,
  • _ R35 represent,s _R10 , SO,-R COR or CONHR
  • E represents a bond, S(O), 0 or NR
  • W., W 2 , W 3 and W 4 independently represent C or N;
  • a further preferred embodiment provides a compound of Formula I wherein, A represents
  • R 1 represents OH, O-Ph, COOH, or P(O) (OH) 2 ;
  • R ,20 represents H, C x _ 2 alkyl, [CH, -optionally substituted aryl, (CH 2 ) . .4 -het; (CH 2 ) .. 4 -N (R ) 2 , (CH 2 ) . .4 -CON(R ,1 l 0 u ), 2 , (CH 2 )._ 4 -
  • X and Y independently at each occurance are selected from NH, N, C, or CH, such that at least one of X and Y always represents N or NH ;
  • Z represents C or N; provided that, (i) when Z represents N, R 7 represents H or
  • R 1 represents OH, -COOH, and O-P(O) (OH) 2 ;
  • R 2 and R independently represent halogen, H, C._ 4 alkyl, Ph, toluyl, OH, 0-(CH 2 ).
  • R 5 represents H
  • R ⁇ represents H
  • R 9 represents H or halogen
  • R 20 represents H.
  • A represents
  • X and Y represent N.
  • R 1 represents OH, or COOH
  • R 2 represents H, halogen, OH, phenyl, 0- (CH 2 ) , .3 -Ph, imidazolyl, 5-amidino benzimidazolyl, 0- (CH.) ._ 2 -C (0) -NH-C._, alkyl, or 0-CH 2 -C (0) -NH-CH 2 -Ph;
  • R 3 represents H, 0-CH 2 -C00H, 0-CH 2 -C (0) 0-C 2 H 5 , 0-CH 2 -C(0)-
  • R 4 represents H, -CH 3 , halogen, 10
  • R represents H;
  • R ⁇ represents H;
  • R 8 represents H, Cl, F, OH or OCH. ;
  • R 9 represents H
  • R 13 and R 14 independently at each occurance represents H, halogen, -OC ⁇ . alkyl, -OH, -CF 3 , or -C._ 4 alkyl;
  • R 15 represents H
  • R , 20 ⁇ represents H or -CH 2 -Ph.
  • X represents C; and Y represents NH.
  • a preferred embodiment of this aspect of the present invention provides compounds wherein R 1 represents -OH, -COOH, or P(O) (OH) 2 ;
  • R 2 represents H, halogen, R 10 , -aryl, heteroaryl, -C._ 2 - alkyl, COOH, -0C._ 2 -alkyl, -0- (CH 2 ) 02 -aryl , or -C 6 _ 10 aryl-C._ 4 alkyl ;
  • R 3 represents H or -0- (CH 2 ) ._ 3 -COOH; alternatively R 2 and R 3 taken together represent
  • R 4 represents H, -C._ 4 alkyl, - (CH 2 ) ._ 4 -C00H, - (CH 2 ) 14 -C00C._ 2 - alkyl, halogen, - (CH 2 ) ._ 2 -C0NH 2 , -C0NH 2 , -N0 2 , -0-C ⁇ alkyl, or -OH;
  • R 5 represents H, -C ⁇ 3 alkyl, - (CH 2 ) ._ 4 -C (0) -NH- (CH 2 ) ,_ 3 - heteroaryl, - (CH 2 ) ,_ 4 -C (0) -NH-CH 3 , or -COOH;
  • R 6 represents H, halogen, or -C. 3 alkyl;
  • R 8 represents H, or halogen
  • R 20 represents H, - (CH 2 ) ._ 4 -Ph-N (S0 2 -C._ 2 alkyl) , - (CH 2 ) ._ 4 -NR 10 -
  • Specifically preferred compounds of the present invention are selected from
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I a pharmaceutically acceptable salt thereof.
  • present invention also provides a method for treating or preventing a thromboembolic disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of
  • novel compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. Described herein are some of the preferred synthetic methods for synthesizing novel compounds of the present invention. All temperatures reported herein are in degrees Celsius, unless indicated otherwise .
  • the novel compounds of Formula I can be prepared using the reactions and synthetic techniques described below. It should be noted that compounds of Formula I include compounds of Formula la. These compounds of Formula la represent some of the novel compounds of the present invention and can be further transformed to provide other novel compounds of the present invention.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 20 are as defined in the detailed description of the invention.
  • the aldehydes represented by structures . 3, 5, 8, 10, and 13 and the carboxylic acids represented by structures 44, 48 . , and 53 . and 5_5 are useful intermediates in the synthesis of the novel compounds of Formulae I and Formula la.
  • the aldehydes and carboxylic acids useful in the synthesis of compounds of Formula I either are commercially available or can be prepared by the synthetic schemes outlined below.
  • Schemes I-IX illustrate the synthesis of aldehydes which can be used to synthesize compounds of Formula I.
  • Scheme I is a representative example of the synthesis of aldehyde 3 using the Mitsunobu reaction.
  • the general procedure comprises mixing an appropriately substituted benzaldehyde, 1, with a Boc protected piperidinol in the presence of triphenyl phosphine in an inert solvent, such as THF, at temperatures ranging from -25° to ambient temperature, preferably 0°.
  • THF inert solvent
  • DEAD diethyl azido dicarboxylate
  • the resulting reaction mixture is stirred at room temperature for 2 to 24 hours after which time the reaction mixture is concentrated under reduced pressure to yield a residue of the desired aldehyde, 3_.
  • Purification of the desired aldehyde can be accomplished by using methods such as chromatography, recrystallization or other methods known to one skilled in the art.
  • R la is hydrogen or the same as R 1 .
  • Scheme II outlines the synthesis of aldehyde 5.
  • the procedure involved forming a reaction mixture by combining an appropriate benzaldehyde 1, such as 4- hydroxy benzaldehyde, ethyl bromoacetate, 4, potassium carbonate and sodium iodide, in an inert solvent, preferably acetone.
  • the reaction mixture is stirred at ambient temperature for 12 to 24 hours after which time the reaction mixture is filtered through celite, and concentrated under reduced pressure to yield an oily residue. This residue can be purified by column chromatography to yield the desired aldehyde, 5.
  • Scheme III represents a general procedure for preparing aldehydes of formula 8 .
  • the procedure comprises mixing 4-hydroxy benzaldehyde 6, substituted thiazole 7, sodium carbonate, cesium carbonate, and sodium iodide in an inert solvent, such as acetone, to form a reaction mixture which is refluxed for eighteen hours.
  • the reaction mixture is cooled to room temperature, filtered through celite, and the filtrate evaporated to yield a residue.
  • the residue is dissolved in ethyl acetate and washed, in succession, with 2% aqueous sodium hydroxide, water, and brine solution. This washed organic layer is concentrated to yield the desired aldehyde 8 . .
  • Scheme IV depicts a method of preparing aldehyde, 10.
  • This method comprises reacting a N,N- dimethylformamide (DMF) solution of a hydroxy benzaldehyde, 11, with sodium hydride at about 0° followed by drop wise addition (about 1 mL per minute) of a DMF solution of dicyanonitrobenzene 9.
  • the resulting mixture is stirred from 12 to 24 hours followed by cautious pouring of the reaction mixture in ice water to yield a product.
  • the product is collected by filtration, dried, and purified by recrystallization, e.g., from ethyl acetate, to yield aldehyde 10.
  • Scheme V depicts a method of preparing aldehyde 13.
  • an aldehyde of formula 11 wherein R 3 , R 4 . and R 5 are hydrogen, i.e., 2 , 3-dihydroxybenzaldehyde (0.6g, 4.3 mmol) was added to dimethyl sulfonamide (DMSO) (10 ml) containing sodium hydride (0.25g, 10.4 mmol).
  • DMSO dimethyl sulfonamide
  • benzyl bromide 0.52 ml, 4.3 mmol
  • DMSO dimethyl sulfonamide
  • aqueous solution then was acidified with 6N hydrochloric acid to adjust the pH from 2 to about 4 and extracted with chloroform (3x).
  • the latter organic layers were washed with IN hydrochloric acid and filtered over silica gel to give 3-benzyloxy-2-hydroxy benzaldehyde .
  • Scheme VI depicts a method for preparing aldehyde 15.
  • Scheme VII illustrates the synthesis of benzyl protected aldehydes 17.
  • the brown oil is purified by flash chromatography (50% ethyl acetate/ hexanes) to afford 0.29 g (66%) of 2-hydroxy-3- (2- pyridin-2-ylethoxy) benzaldehyde 17 as a light yellow solid.
  • Scheme IX illustrates the preparation of aldehydes 21.
  • a compound of formula ,20 wherein R 3 , R 4 and R 5 are hydrogen, i.e., 3- (3 -hydroxyphenyl) propionic acid, (3.0 g, 0.018 mol, Aldrich Chemical Comp, Cat 1279), NaOH (6 g, 0.15 mol), water (40 mL) , and chloroform (40 ml) were combined and heated at 70°C for 12 h in a 100 ml round bottom flask.
  • Compound 22 was prepared by combining terephthaldehyde monodiethylacetal (Acros Chemical Comp. Cat #24069-1000, 5.0 g, 0.02 mol), malononitrile (1.32 g, 0.02 mol), EtOH ( 30 mL) , and NaOEt ( 2.72 g, 0.04 mol). The mixture was stirred at ambient temperature for 12 h, water (50 mL) was added, and the mixture was extracted with Et 2 0 (2x 50 mL) . The organic layer was dried (MgS0 4 ) , filtered and concentrated under reduced pressure to give 22 in a 88% yield (4.5 g, 0.017 mol).
  • Scheme X shows a representative example of the synthesis of carboxylic acid 44.
  • a mixture of a compound of formula 4_0 wherein R 3 and R 4 are hydrogen and R 5 is chloro, i.e., 5- chloro-2-hydroxy benzoic acid, (5.0 g, 29 mmol) and N- iodosuccinimide (7.17 g, 32 mmol) in acetic acid (30 mL) was heated to 95° C for 2 h. Additional N-iodosuccinimide (0.70 g, 3.1 mmol) was added and heating was continued for 1 h. The mixture was cooled and poured over ice.
  • Scheme XI shows a method incorporating a Mitsonobu reaction for the synthesis of carboxylic acid 48.
  • Triphenylphosphine (1.80g, 6.86 mmol) was added to the solution followed by addition of diethylazodicarboxylate (1.1 mL, 6.9 mmol) over 5 min. After 30 min, the reaction mixture was warmed to room temperature and stirred for 6 h. Partial evaporation gave a concentrated crude material which was directly loaded onto a flash chromatography column (non-linear gradient 0-20-35% EtOAc in hexanes) to give 1.62 g (65%) of tert-butyl 2- (2 , 2-dimethyl-4-oxo-4 , 4- benzo [1,3] dioxin-8-yloxymethyl) pyrrolidine-1-carboxylate 47 as an oil.
  • tert-butyl-2- (2, 2-dimethyl-4-oxo-4 , 4- benzo [1,3] dioxin-8-yloxymethyl ) pyrrolidine-1-carboxylate 47 (1.65 g, 4.54 mmol) was dissolved in DMSO (9.5 mL) and then 49% aqueous KOH (1.5 mL) was added to the solution to form a basic reaction mixture. This basic reaction mixture was heated at 60°C for 40 min. After cooling to room temperature and addition of 0.5 M aqueous KHS0 4 (100 mL) gave an acidic suspension.
  • Scheme XII illustrates a method for the synthesis of carboxylic acid 53.
  • Scheme XIII illustrates the synthesis of a diacid used to make compounds of carboxylic acid 55.
  • Scheme XX outlines general procedures (Method A) for the synthesis of compounds of Formula la.
  • Scheme XX requires refluxing a mixture of diaminobenzamidine monohydrochloride with an aldehyde in the presence of an oxidizing agent (e.g., benzoquinone, sodium metabisulfite, and the like) in ethanol for about 12 hours. The mixture is then cooled to room temperature and poured into acetonitrile. This results in the generation of the desired product of Formula la which is further washed with fresh acetonitrile and dried.
  • an oxidizing agent e.g., benzoquinone, sodium metabisulfite, and the like
  • Example 200 uses the acid from Scheme XIII which is reacted with 3 , 4 , -diaminopyridine in the presence of polyphosphoric acid (Method B, Scheme XXI) . The resultant compound is then reduced and appropriately substituted to yield Example 200.
  • Table 2 lists examples of compounds of Formula I (and la) prepared by the above synthetic schemes XX and XXI, methods A and B respectively.
  • Table 2 Lists some of the benzimidazole compounds represented by Formula I .
  • R , R , R and R represent hydrogen; and R represents amidino (or guanidino in the case of Example 100) .
  • Compounds of Formula I in which any of R 2 , R 3 , R 4 and R 5 are amino can be prepared by reducing a corresponding compound of Formula la in which R 2 , R 3 , R 4 or R 5 nitro.
  • the reduction can be accomplished in any number of ways known to one skilled in the art.
  • a representative way of reducing the nitro group is by catalytic hydrogenation.
  • the catalytic hydrogenation is carried out by mixing an appropriate nitro compound of Formula I with Pearlman ' s catalyst in a suitable solvent (e.g., methanol) . Air from the reaction vessel is removed under reduced pressure and the reaction vessel is then charged with an atmosphere of hydrogen.
  • Compounds of Formula I in which any of R 2 , R 3 , R 4 and R 5 comprise groups containing an annular nitrogen atom may be further derivatized to an corresponding N-1-iminoethyl substituted derivative by reacting the compound with ethyl acetamidate.
  • a compound of Formula I in which R 4 is 4- ( 1- (1-iminoethyl) piperindin-4- yloxy) benzylamino can be prepared by reacting a corresponding compound of Formula I in which R 4 is 4- piperidin-4-yloxybenzyl amino with ethyl acetamidine hydrochloride and triethyl amine in ethanol and stirring over night under a nitrogen atmosphere. The reaction mixture is concentrated under reduced pressure and residue may be purified by column chromatography.
  • Compounds of Formula I in which any of R 2 , R 3 , R 4 and R 5 are or contain a carboxy group can be prepared by hydrolyzing a corresponding compound of Formula la in which R 2 , R 3 , R 4 or R 5 is or contains a -COOR 10 group.
  • a compound of Formula I in which R 3 is carboxymethoxy can be prepared by hydrolyzing a compound of Formula I in which R 3 is ethoxy carbonyl methoxy.
  • Compounds of Formula I in which Q, Q 1 , Q 2 and/or Q 3 or L 1 , L 2 , L 3 and/or L 4 are N-R 37 can be prepared by reacting a corresponding compound of Formula I in which Q, Q 1 , Q 2 and/or Q 3 or L 1 , L 2 , L 3 and/or L 4 is NH with a suitable protected amino acid.
  • the reaction is typically carried out in the presence of a coupling agent (e.g., PyBOP, CDI , and the like) .
  • Example 139 For example a compound of Formula I in which R 2 is 1-aminoacetyl pyrrolidin-3yloxy was prepared by coupling a PyBrOP peptide onto Example 139, Table 2 to give the product Example 208, Table 2a.
  • Example 139 (Table 2), were suspended in DMF (1.0 mL) under a N 2 atmosphere. Diisopropylethylamine was added and the mixture was cooled in a water/ice bath at 0°C . PyBrOP was quickly added to the cold suspension.
  • R 2 is methyl sulfonyl amino
  • Hunig's base (0.042 mL, 0.24 mmol) was added to a suspension of 2- [2-Hydroxy-3- (4 , 5 , 6 , 7-tetrahydro-3H- imidazo [4 , 5-c] pyridin-2-yl) -phenyl] -lH-benzoimidazole-5- carboxamidine 75 (19mg, 0.04 mmol) and lH-pyrazole-1- carboxamidine hydrochloride (12 mg, 0.082 mmol) in anhydrous DMF and the mixture was stirred for 12-18 h at 80 °C . The mixture was poured into water (15 mL) / diethyl ether (15 mL) .
  • Example 285 Table 2a To a cold (0°C) solution of 2- (5-amino-2-hydroxy- phenyl ) -3H-benzimidazole-5-carboxamdine dihydro- chloride (0.203 g, 0.6 mmol) in dry pyridine under nitrogen is added methane sulfonyl chloride (93 uL, 1.2 mmol) dropwise. After stirring the solution for 12-18 h followed by warming it to ambient temperature the solvent is removed and the residue is purified by reverse phase HPLC. Appropriate fractions were lyophilized to an off white solid. (125 mg, 60% yield) .
  • R 1 is OH; and R 5 , R 6 , R 8 , R 9 and R 20 represent hydrogen .
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 20 are as described in the detailed description.
  • Compounds of Formula I having the indole nucleus can be synthesized by using commercially available ketones or carboxylic acids, for example compounds 210 to 237 , and aldehyde compounds 240 (a) to 240 (e) which can be prepared by schemes LI through LXI. discussed below.
  • Scheme LI illustrates the general procedure for condensation of acetophenones and substituted aromatic aldehydes, wherein R 1 , R 2 , R 3 , R 4 and R 5 are as described in the detailed description section above.
  • Scheme LII illustrates synthesis of ketones 210, wherein R 1 , R 2 , R 3 , and R 5 are as defined in the detailed description section above.
  • the carboxylic acid 209 for example 3- [4-Hydroxy-3-
  • Scheme LIII illustrates the synthesis of ketones 212 to 216.
  • Synthesis of 215 and 216 can be accomplished by following the procedures outlined for 213 and 214 respectively.
  • Scheme LIV illustrates synthesis of 220 which is useful in synthesizing compounds of Formula I.
  • N-methoxy-N-methyl-2-hydroxy-3-phenylbenzamide (219, 2.37 g, 9.2 mmol) is dissolved in dry THF (40 ml) under nitrogen and cooled to 0°C in an ice bath.
  • MeMgBr (6.5 ml,
  • Example 522 Table Ilia: Prepared according to literature procedure: Sipos, G.; Szalo, R. Acta Physica et Chemica, Vol. 7, 1961, pp. 126-128.
  • the title compound 515 is prepared by bromination of 2 ' -hydroxy-1-methyl acetophenone using the procedure for 503, above.
  • Example 502 Table Ilia (Scheme LV) 221 is prepared by the condensation procedure described in Scheme Ll above .
  • Example 510 Table Ilia: General procedure for acetylation at the 2-position of phenols:
  • the aryl acetate (225) and AlCL 20 mmol each) were heated for 2 hours at 150 C.
  • the reaction mixture is then diluted with HCl and water to yield the 226.
  • the product is filtered and dried under reduced pressure.
  • Example 513, Table Ilia The title compound is prepared from ex. 525 by alkylation with benzyl bromide using the procedure described for ex. 517, Table Ilia.
  • Example 504 The title compound is prepared from ex. 510 by alkylation with benzyl bromide using the procedure described for ex. 517, Table Ilia.
  • Example 512 Table Ilia: The title compound is prepared from 4-cyano phenol as shown in Scheme LVII below:
  • Step 1 and 2 are as described in Scheme LVI above.
  • Step 3 is as described in Scheme LII above.
  • N-chloro succinimide (NCS) (12mmol) and l-benzyl-2 ' -hydroxy acetophenone (10 mmol) are heated at 70° in methanol for two weeks. The mixture is then extracted with ether, and washed with water and concentrated to yield the title compound (1.8 g) . The product is purified by flash chromatography on silica column using 1:3 diethyl ether : hexanes mixture.
  • Scheme LVIII is a method that involves using a Suzuki coupling to generate substituted acetophenones (Example 519, Table Ilia) .
  • 2 ' -Hydroxy-3 ' -bromo-5 'methylacetophenone 233 can be treated as follows: LDA (20 mL, 1.5 M) is slowly added to a THF solution of 233 at about 0° and the reaction mixture is then cooled to about -78° followed by the addition of bromo acetonitrile (40 mmol) . This resulting reaction mixture is stirred for 12-18 h at -78° and is then quenched with IN HCl followed by extraction with ether. The ether layer is washed with water, dried (MgS0 4 ) and concentrated to yield an oil. This oil is purified by flash chromatography (4:1; hexanes : ethyl acetate) to yield 1 g of 235. (Example 517, Table Ilia)
  • Acetyl chloride (14.7 ml, 5 eq. ) is added slowly to an ice cooled suspension of A1C1 3 (27.7 g, 5 eq. ) in dry CH 2 C1 2 (125 ml) .
  • the reaction is stirred until most of the solid is dissolved, then 5-methyl salicylic acid 236 (6.31 g, 41 mmol) is added.
  • the reaction is stirred at 0°C for 1.5 hr, then at room temperature for 1.5 hr .
  • the reaction is poured onto ice, diluted with Et 2 0, and washed with water, brine, dried (MgS04) . Concentration in vacuo afforded a slowly crystallizing oil.
  • Aldehyde compounds useful in the synthesis of Indole based compounds of Formula I are commercially acailable. They can also be prepared by schemes LX(1) to LX(5) outlined below.
  • the acidified mixture then was extracted with ether or ethyl acetate, the combined organic layers were washed with water, brine, and dried (Na 2 S0 4 ) .
  • the dried organic phase was concentrated to yield the title compound as an oil (54.6 gm. , 92%) .
  • the aldehyde 240 (d) was prepared using the procedure outlined in Scheme X above.
  • Compounds analogous to 240 (d) with different substituents can be prepared by following the procedure in Scheme LX(4) above.
  • R 20a generally comprises an extra methylene group than R 20 , thus one can represent R 20a as CH,-R
  • R 1 represents OH
  • R 5 represents H
  • R 8 is Cl; R 6 and R 9 are as defined in the detailed description.
  • Me 3 Al/NH 4 Cl solution can be prepared by adding 5g of ammonium chloride to p-xylenes (100ml) at 0°C, then adding a 2M solution of trimethylaluminum in toluene
  • Example 841 Table III: A mixture of 4- ⁇ N ' - [1- (3-bromo-2- hydroxy-5-methyl-phenyl) -3- (4-nitro-phenyl) -propylidene] - hydrazino ⁇ -benzamidine 202 (0.30 g, 0.0006 mol) and PPA (5 L) was heated at 130°C (temperature may vary between 125 - 180 °C) for 30 min (reaction times may vary between 30 minutes - 4 h) . The reaction mixture was cooled to ambient temperature and cold H 2 0 (5 mL) was added to produce a precipitate. The precipitate was washed and taken up in 0. IN HCl.
  • the methyl ester from above (126 mmol, 21g) was dissolved in acetonitrile (650 mL) to form a solution. This solution was mixed with triethylamine (3.4 eq, 60 ml), magnesium dichloride (1.6 eq, 19.7 g) , paraformaldehyde in several portions (6.8 eq, 26 gr) to form a yellow mixture. The yellow mixture was refluxed for 3.5 hours at which time TLC revealed that all the starting material was consumed. The reaction mixture was acidified with 6 N HCl, concentrated and extracted with ether (3x150 ml) . The ether extracts were washed with water, brine, dried (Na 2 SOJ and concentrated to yield 23.6g (96%) of crude product.
  • Acetic anhydride (1.1 eq, 0.77ml, in 7 ml of AcOH) was added drop wise to a stirring solution of 3g of 18 in 34 ml of acetic acid at ambient temperature under N 2 over several minutes. HPLC 15 minutes thereafter indicated formation of a hydrophobic product.
  • a catalytic amount of Pd/C (10% w/w) was added to the reaction mixture and teh reaction vessel then was charged with H 2 (atm. ) .
  • the reaction mixture was agitated for about 1.5h.
  • the agitated reaction mixture was passed through a celite pad (rinsed with AcOH) .
  • the filtrate was diluted with ethyl acetate to yield a precipitate.
  • the colid was isolated and dried in vacuo to yield 2.05g of the crude amdidine.
  • the cyano-indole was dissolved in 300 ml dry EtOH in a 1 L flask fitted with a drying tube. Twenty (20) equivalents of hydroxylamine ' HCl (54g) and K 2 C0 3 (107g) were added and the mixture refluxed overnight. The product was observed by HPLC as was a significant amount of the starting indole. An additional 10 eq of both hydroxylamine ' HCl and K 2 C0 3 were added and the reaction mixture refluxed for an additional 8- 12h. HPLC indicated the reaction had progressed, with about 5% of the starting material remaining. The solid was separated and the filtrate concentrated to yield residue. The residue was diluted with ethyl acetate, washed with water, the organic layer was dried (Na 2 S0J and concentrated under reduced pressure to yield compound 260.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés de formule (I), A-B, ainsi que leurs promédicaments ou leurs sels pharmaceutiquement acceptables, où A représente une structure à noyau hétérocyclique, bicyclique saturée, non saturée ou partiellement non saturée, et où B représente un groupe aryle ou hétéroaryle. Les composés préférés de l'invention comportent un noyau de benzimidazole ou d'indol. Les composés de cette invention sont des inhibiteurs des sérine protéases, de l'urokinase (uPA), du facteur Xa et/ou du facteur VIIa (FVIIa), et conviennent en tant qu'agents anticancéreux et/ou en tant qu'anticoagulants destinés à la prophylaxie ou à la thérapie d'affections thromboemboliques chez les mammifères.
EP99968917A 1998-12-18 1999-12-17 Derives bicycliques (hetero)aryl aryl, leur preparation et leur utilisation comme inhibiteurs de protease Withdrawn EP1140859A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US11300798P 1998-12-18 1998-12-18
US113007P 1998-12-18
PCT/US1999/030302 WO2000035886A2 (fr) 1998-12-18 1999-12-17 Inhibiteurs de proteases

Publications (1)

Publication Number Publication Date
EP1140859A2 true EP1140859A2 (fr) 2001-10-10

Family

ID=22347074

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99968917A Withdrawn EP1140859A2 (fr) 1998-12-18 1999-12-17 Derives bicycliques (hetero)aryl aryl, leur preparation et leur utilisation comme inhibiteurs de protease

Country Status (20)

Country Link
US (1) US6867200B1 (fr)
EP (1) EP1140859A2 (fr)
JP (1) JP2002532479A (fr)
KR (1) KR20010086119A (fr)
CN (1) CN1344256A (fr)
AU (1) AU779117B2 (fr)
BR (1) BR9916363A (fr)
CA (1) CA2355249A1 (fr)
CZ (1) CZ20012006A3 (fr)
EA (1) EA200100675A1 (fr)
EE (1) EE200100323A (fr)
HU (1) HUP0104987A3 (fr)
IL (1) IL143801A0 (fr)
NO (1) NO20012980L (fr)
NZ (1) NZ512375A (fr)
PL (1) PL349192A1 (fr)
SK (1) SK7972001A3 (fr)
TR (1) TR200102533T2 (fr)
UA (1) UA70976C2 (fr)
WO (1) WO2000035886A2 (fr)

Families Citing this family (96)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2415742A1 (fr) * 2000-07-25 2002-01-31 Merck & Co., Inc. Indoles n-substitues utiles pour le traitement du diabete
US6465503B2 (en) * 2000-08-11 2002-10-15 Axys Pharmaceuticals, Inc. Selective urokinase inhibitors
WO2002062829A1 (fr) 2001-02-02 2002-08-15 Chugai Seiyaku Kabushiki Kaisha Derives de peptide
SE0100902D0 (sv) 2001-03-15 2001-03-15 Astrazeneca Ab Compounds
JP2004535411A (ja) 2001-05-25 2004-11-25 ブリストルーマイヤーズ スクイブ カンパニー マトリックスメタロプロテナーゼ及び／またはＴＮＦ−α転換酵素（ＴＡＣＥ）の阻害剤としてのヒダントイン及び関連複素環化合物
WO2003006670A2 (fr) * 2001-07-09 2003-01-23 Axys Pharmaceuticals, Inc. Derives de l'acide 2-[5-(5-carbamimidoyl-1h-heteroaryl)-6-hydroxybiphenyl-3-yl]-succinique en tant qu'inhibiteurs du facteur viia
EA007339B1 (ru) 2001-07-27 2006-08-25 Кьюэрис, Инк. Медиаторы путей передачи сигналов генами hedgehog, содержащие их композиции и способы применения указанных веществ
EP1425015A4 (fr) * 2001-08-20 2004-12-15 Bristol Myers Squibb Co Derives de tetrahydroquinoline utilises comme agents antithrombotiques
SE0103710D0 (sv) 2001-11-07 2001-11-07 Astrazeneca Ab Compounds
CA2474195A1 (fr) * 2002-02-13 2003-08-21 Axys Pharmaceuticals, Inc. Derives 2-[5-(5-carbamimidoyl-1h-heteroaryl)]-6-hydroxybiphenyl-3-yl comme inhibiteurs du facteur viia
US6867320B2 (en) 2002-02-21 2005-03-15 Asahi Kasei Pharma Corporation Substituted phenylalkanoic acid derivatives and use thereof
JP2005520858A (ja) 2002-03-20 2005-07-14 メタボレックス， インコーポレイテッド 置換フェニル酢酸
WO2004010996A1 (fr) * 2002-07-29 2004-02-05 Shizuoka Coffein Co., Ltd. Derive 1,3 azole et composition medicale contenant ce derive pour le traitement de thrombose
SE0202539D0 (sv) * 2002-08-27 2002-08-27 Astrazeneca Ab Compounds
BR0313825A (pt) 2002-08-29 2005-07-12 Merck & Co Inc Composto, composição farmacêutica, método para tratar de diabete mellitus tipo 2 em um mamìfero, e, uso de composto
ES2543588T3 (es) 2002-12-03 2015-08-20 Pharmacyclics Llc Derivados de 2-(2-hidroxibifenil-3-il)-1H-benzoimidazol-5-carboxamidina como inhibidores del factor VIIa
WO2004062661A1 (fr) * 2003-01-08 2004-07-29 Axys Pharmaceuticals, Inc. Derives d'acide 2[-5-(5-carbamimidoyl-1h-heteroaryl)-6-hydroxybiphenyl-3-yl] carboxylique comme inhibiteurs du facteur viia
KR20110010824A (ko) 2003-01-14 2011-02-07 아레나 파마슈티칼스, 인크. 대사 조절제로서의 １,２,３-삼치환된 아릴 및 헤테로아릴 유도체, 및 당뇨병 및 고혈당증을 비롯한 이에 관련된 장애의 예방 및 치료
US7129264B2 (en) 2003-04-16 2006-10-31 Bristol-Myers Squibb Company Biarylmethyl indolines and indoles as antithromboembolic agents
US7199259B2 (en) 2003-06-20 2007-04-03 Metabolex, Inc. Resolution of α-(phenoxy)phenylacetic acid derivatives
MXPA06001739A (es) 2003-08-14 2006-05-12 Asahi Kasei Pharma Corp Derivado de acido arilalcanoico substituido y uso del mismo.
US7417063B2 (en) 2004-04-13 2008-08-26 Bristol-Myers Squibb Company Bicyclic heterocycles useful as serine protease inhibitors
KR20070036076A (ko) 2004-05-25 2007-04-02 메타볼렉스, 인코포레이티드 Ｐｐａｒ의 조절제로서의 치환된 트리아졸 및 이의제조방법
EP1761504A2 (fr) * 2004-06-02 2007-03-14 Pharmacyclics, Inc. Inhibiteur de facteur viia
US8729117B2 (en) 2004-06-02 2014-05-20 Pharmacyclics, Inc. Factor VIIa inhibitor
CA2569170A1 (fr) * 2004-06-02 2005-12-22 Pharmacyclics, Inc. Inhibiteur du facteur viia
US7648992B2 (en) 2004-07-05 2010-01-19 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
US7781478B2 (en) 2004-07-14 2010-08-24 Ptc Therapeutics, Inc. Methods for treating hepatitis C
JP5173192B2 (ja) * 2004-09-30 2013-03-27 武田薬品工業株式会社 プロトンポンプ阻害薬
SE0403085D0 (sv) 2004-12-17 2004-12-17 Astrazeneca Ab Novel componds
SE0403086D0 (sv) 2004-12-17 2004-12-17 Astrazeneca Ab Compounds
US7714131B2 (en) 2005-09-23 2010-05-11 Metabolex, Inc. Process for the stereoselective preparation of (−)-halofenate and derivatives thereof
US8629147B2 (en) * 2005-11-03 2014-01-14 Chembridge Corporation Heterocyclic compounds useful in the treatment of neoplastic diseases, inflammatory disorders and immunomodulatory disorders
KR20080103584A (ko) 2006-03-30 2008-11-27 아사히 가세이 파마 가부시키가이샤 치환 이환식 환상 유도체 및 그 용도
JP5323063B2 (ja) 2007-05-31 2013-10-23 塩野義製薬株式会社 オキシイミノ化合物およびその使用
WO2008155540A1 (fr) * 2007-06-19 2008-12-24 Eh Europe Gmbh Procédé de fabrication d'électrode, électrode et accumulateur comprenant l'électrode
WO2009052323A2 (fr) * 2007-10-16 2009-04-23 Pharmacyclics, Inc. Fabrication, compositions et utilisations d'un modulateur du facteur de coagulation viia
CN102015656A (zh) 2008-04-28 2011-04-13 旭化成制药株式会社 苯丙酸衍生物及其用途
WO2009151152A1 (fr) 2008-06-11 2009-12-17 Shionogi & Co., Ltd. Composés oxycarbamoyle et leur utilisation
AR072297A1 (es) 2008-06-27 2010-08-18 Novartis Ag Derivados de indol-2-il-piridin-3-ilo, composicion farmaceutica que los comprende y su uso en medicamentos para el tratamiento de enfermedades mediadas por la sintasa aldosterona.
CN101654427B (zh) * 2008-08-19 2012-12-05 信谊药厂 抗凝化合物、组合物及其用途
KR101354418B1 (ko) * 2009-07-30 2014-01-23 단국대학교 산학협력단 형광 탐지자 및 이의 제조 방법
BR112013008100A2 (pt) 2010-09-22 2016-08-09 Arena Pharm Inc "moduladores do receptor de gpr19 e o tratamento de distúrbios relacionados a eles."
TWI527814B (zh) * 2010-12-16 2016-04-01 健生科學愛爾蘭無限公司 作為呼吸道融合病毒抗病毒劑之氮雜苯并咪唑類
TWI541241B (zh) * 2010-12-16 2016-07-11 健生科學愛爾蘭無限公司 作為呼吸道融合病毒抗病毒劑之咪唑并吡啶類
TWI515187B (zh) 2010-12-16 2016-01-01 健生科學愛爾蘭無限公司 作為呼吸道融合病毒抗病毒劑之吲哚類
TWI501967B (zh) 2010-12-16 2015-10-01 Janssen R&D Ireland 作為呼吸道融合病毒抗病毒劑之氮雜吲哚類
WO2012149048A1 (fr) 2011-04-26 2012-11-01 Indiana University Research And Technology Corporation Inhibiteurs de la tyrosine phosphatase et leurs utilisations pour moduler l'activité de la protéine lyp
CA2873920C (fr) 2012-06-15 2021-07-20 Janssen R&D Ireland Derives de 1,3-dihydro-2h-benzimidazol-2-one substitue d'heterocycles comme agents antiviraux contre le virus respiratoire syncytial
EP2977374A1 (fr) * 2014-07-21 2016-01-27 Université de Strasbourg Molécules présentant des propriétés d'émission double
MX368296B (es) * 2014-09-30 2019-09-27 Transitions Optical Inc Absorbentes de luz ultravioleta.
EP3242666A1 (fr) 2015-01-06 2017-11-15 Arena Pharmaceuticals, Inc. Procédés de traitement de maladies associées au récepteur s1p1
WO2016205590A1 (fr) 2015-06-18 2016-12-22 Cephalon, Inc. Dérivés de 4-benzyl et 4-benzoyl-pipéridine substitués
PE20180572A1 (es) 2015-06-18 2018-04-04 Cephalon Inc Derivados de piperidina 1,4-sustituidos
KR20230160955A (ko) 2015-06-22 2023-11-24 아레나 파마슈티칼스, 인크. Ｓ1ｐ1 수용체-관련 장애에서의 사용을 위한 (ｒ)-2-(7-(4-시클로펜틸-3-(트리플루오로메틸)벤질옥시)-1,2,3,4-테트라히드로시클로-펜타[ｂ]인돌-3-일)아세트산 (화합물 1)의 결정성 ｌ-아르기닌 염
ES2928164T3 (es) 2015-10-19 2022-11-15 Incyte Corp Compuestos heterocíclicos como inmunomoduladores
KR102547771B1 (ko) * 2015-11-09 2023-06-26 고려대학교 산학협력단 4-치환된-2-(5-치환된-1h-인돌-2-일)페놀 유도체, 그 제조방법 및 이를 포함하는 세포 증식 및 전이 억제용 약학 조성물
LT3377488T (lt) 2015-11-19 2023-01-10 Incyte Corporation Heterocikliniai junginiai, kaip imunomoduliatoriai
BR112018012756A2 (pt) 2015-12-22 2018-12-04 Incyte Corp compostos heterocíclicos como imunomoduladores
MA44860A (fr) * 2016-05-06 2019-03-13 Incyte Holdings Corp Composés hétérocycliques utilisés comme immunomodulateurs
WO2017205464A1 (fr) 2016-05-26 2017-11-30 Incyte Corporation Composés hétérocycliques utilisés comme immunomodulateurs
CN105884673B (zh) * 2016-06-03 2018-05-11 温州大学 一种吲哚衍生物的合成方法
SI3472167T1 (sl) 2016-06-20 2022-11-30 Incyte Corporation Heterociklične spojine kot imunomodulatorji
US10071079B2 (en) 2016-06-29 2018-09-11 Bristol-Myers Squibb Company [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
US20180016260A1 (en) 2016-07-14 2018-01-18 Incyte Corporation Heterocyclic compounds as immunomodulators
CA3031675A1 (fr) 2016-07-30 2018-02-08 Bristol-Myers Squibb Company Composes d'indole substitues par du dimethoxyphenyle comme des inhibiteurs de tlr7, tlr8 ou tlr9
US20180057486A1 (en) 2016-08-29 2018-03-01 Incyte Corporation Heterocyclic compounds as immunomodulators
KR102519535B1 (ko) 2016-09-09 2023-04-06 브리스톨-마이어스 스큅 컴퍼니 피리딜 치환된 인돌 화합물
EP3558973B1 (fr) 2016-12-22 2021-09-15 Incyte Corporation Dérivés pyridine utilisés en tant qu'immunomodulateurs
AU2017382870B2 (en) 2016-12-22 2022-03-24 Incyte Corporation Benzooxazole derivatives as immunomodulators
CN110267953B (zh) 2016-12-22 2022-12-20 因赛特公司 四氢咪唑并[4,5-c]吡啶衍生物作为pd-l1内在化诱导剂
US20180179201A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Heterocyclic compounds as immunomodulators
EP3582772A1 (fr) 2017-02-16 2019-12-25 Arena Pharmaceuticals, Inc. Composés et méthodes de traitement de l'angiocholite biliaire primitive
KR102688509B1 (ko) 2017-08-04 2024-07-24 브리스톨-마이어스 스큅 컴퍼니 [1,2,4]트리아졸로[4,3-a]피리디닐 치환된 인돌 화합물
JP7104775B2 (ja) 2017-08-04 2022-07-21 ブリストル－マイヤーズ スクイブ カンパニー Ｔｌｒ７／８／９の阻害剤として有用な置換インドール化合物
EP3710440B1 (fr) 2017-11-14 2023-04-05 Bristol-Myers Squibb Company Composés d'indole substitués
KR20200100687A (ko) 2017-12-15 2020-08-26 브리스톨-마이어스 스큅 컴퍼니 치환된 인돌 에테르 화합물
MX2020006168A (es) 2017-12-18 2020-08-13 Bristol Myers Squibb Co Compuestos de 4-azaindol.
JP7291145B2 (ja) 2017-12-19 2023-06-14 ブリストル－マイヤーズ スクイブ カンパニー Ｔｌｒ阻害剤として有効な置換されたインドール化合物
US11420973B2 (en) 2017-12-19 2022-08-23 Bristol-Myers Squibb Company Amide substituted indole compounds useful as TLR inhibitors
KR20200101956A (ko) 2017-12-19 2020-08-28 브리스톨-마이어스 스큅 컴퍼니 6-아자인돌 화합물
ES2904773T3 (es) 2017-12-20 2022-04-06 Bristol Myers Squibb Co Compuestos de diazaindol
KR20200101400A (ko) 2017-12-20 2020-08-27 브리스톨-마이어스 스큅 컴퍼니 아릴 및 헤테로아릴 치환된 인돌 화합물
EA202091480A1 (ru) 2017-12-20 2020-11-06 Бристол-Маерс Сквибб Компани Аминоиндольные соединения, пригодные в качестве ингибиторов tlr
HRP20230090T1 (hr) 2018-03-30 2023-03-17 Incyte Corporation Heterociklički spojevi kao imunomodulatori
CN112752756B (zh) 2018-05-11 2024-06-25 因赛特公司 作为PD-L1免疫调节剂的四氢-咪唑并[4,5-c]吡啶衍生物
CA3114883A1 (fr) * 2018-10-02 2020-04-09 Disc Medicine, Inc. Inhibiteurs de matriptase 2 et leurs utilisations
EP3870589B1 (fr) 2018-10-24 2023-09-06 Bristol-Myers Squibb Company Composés dimères d'indole substitués
AR119624A1 (es) 2019-08-09 2021-12-29 Incyte Corp Sales de un inhibidor de pd-1 / pd-l1
MX2022003578A (es) 2019-09-30 2022-05-30 Incyte Corp Compuestos de pirido[3,2-d]pirimidina como inmunomoduladores.
BR112022009031A2 (pt) 2019-11-11 2022-10-11 Incyte Corp Sais e formas cristalinas de um inibidor de pd-1/pd-l1
WO2022099018A1 (fr) 2020-11-06 2022-05-12 Incyte Corporation Procédé de préparation d'un inhibiteur de pd-1/pd-l1
PE20231438A1 (es) 2020-11-06 2023-09-14 Incyte Corp Proceso para hacer un inhibidor de pd-1/pd-l1 y sales y formas cristalinas del mismo
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
CN116283896A (zh) * 2022-09-07 2023-06-23 广东晨康生物科技有限公司 一种具有pd-l1抑制活性的联苯类化合物及其用途
CN117430525A (zh) * 2023-03-01 2024-01-23 中化学科学技术研究有限公司 席夫碱配体及其制备方法和应用

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3224512A1 (de) 1982-07-01 1984-01-05 Dr. Karl Thomae Gmbh, 7950 Biberach Neue imidazolderivate, ihre herstellung und diese verbindungen enthaltende arzneimittel
JPS63166588A (ja) * 1986-12-27 1988-07-09 Kanzaki Paper Mfg Co Ltd クロメノ化合物およびクロメノ化合物を用いた感熱記録体
JP2869561B2 (ja) 1989-05-22 1999-03-10 大塚製薬株式会社 血小板粘着抑制剤
US6255091B1 (en) * 1995-04-28 2001-07-03 Axys Pharmaceuticals, Inc. Potentiating metal mediated serine protease inhibitors with cobalt or zinc ions
US6150379A (en) * 1997-11-26 2000-11-21 Axys Pharmaceuticals, Inc. Compounds and compositions as anticoagulants
WO1999026933A1 (fr) 1997-11-26 1999-06-03 Axys Pharmaceuticals, Inc. Derives d'amidinoaryle substitue et leur utilisation comme anticoagulants

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0035886A3 *

Also Published As

Publication number Publication date
PL349192A1 (en) 2002-07-01
IL143801A0 (en) 2002-04-21
BR9916363A (pt) 2001-12-11
NO20012980L (no) 2001-08-01
SK7972001A3 (en) 2002-06-04
UA70976C2 (uk) 2004-11-15
US6867200B1 (en) 2005-03-15
JP2002532479A (ja) 2002-10-02
HUP0104987A3 (en) 2002-09-30
HUP0104987A2 (hu) 2002-07-29
WO2000035886A3 (fr) 2000-10-26
TR200102533T2 (tr) 2006-06-21
CN1344256A (zh) 2002-04-10
WO2000035886A2 (fr) 2000-06-22
CA2355249A1 (fr) 2000-06-22
EE200100323A (et) 2002-08-15
AU2711500A (en) 2000-07-03
EA200100675A1 (ru) 2001-12-24
NO20012980D0 (no) 2001-06-15
CZ20012006A3 (cs) 2002-03-13
NZ512375A (en) 2003-11-28
KR20010086119A (ko) 2001-09-07
AU779117B2 (en) 2005-01-06

Similar Documents

Publication Publication Date Title
WO2000035886A2 (fr) Inhibiteurs de proteases
CA1281329C (fr) Inhibiteurs de la lipoxygenase
US5260316A (en) Isoquinolyl substituted hydroxylamine derivatives
CA2079376C (fr) Indol (heteroaylmethoxy bicyclique) comme inhibiteur de leucotriene biosynthetique
US5350761A (en) Indolyl substituted hydroxylamine derivatives
US20030225036A1 (en) Non-amidine containing protease inhibitors
US5334600A (en) Isoquinolyl substituted hydroxylamine derivatives
KR20080073337A (ko) 옥사졸 화합물 및 제약 조성물
CA2136240A1 (fr) Indoles bicycliques (azaaromatiques) en tant qu'inhibiteurs de la biosynthese de la leucotriene
AU2006292429A1 (en) Carbazole derivatives
US20070254917A1 (en) Intracellular receptor modulator compounds and methods
EP0526402B1 (fr) Hydroxylamine hétéroaryl substituées comme inhibiteurs de lipoxygenase
EP1242366A1 (fr) Salicylamides utiles en tant qu'inhibiteurs des serines proteases
US6825352B2 (en) Preparation and use of ortho-sulfonamido arylhydroxamic acids as matrix metalloproteinase inhibitors
JP2004502754A (ja) ホスファターゼ阻害剤の調製
WO2004046123A1 (fr) Derives de benzoxazole, benzthiazole et benzimidazole utiles en tant qu'inhibiteurs d'heparanase
MXPA01006070A (en) (hetero)aryl-bicyclic heteroaryl derivatives, their preparation and their use as protease inhibitors
EP1276722A1 (fr) Inhibiteur de naphthamidine urokinase
KR20060086367A (ko) 매트릭스-메탈로프로테이나제의 억제제로서 사용된바이사이클릭 이미노산 유도체
EP1259488A1 (fr) Acides ortho-sulfonamido aryl hydroxamiques, procede pour leur preparation et leur utilisation comme inhibiteurs de metalloproteinase de la matrice
CZ20003117A3 (cs) Inhibitory fosfolipázy

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20010622

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

17Q First examination report despatched

Effective date: 20020909

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20051109